Structural Basis for Functional Tetramerization of Lentiviral Integrase

PLoS Pathogens

Alan Engelman¹  Francesca Di Nunzio¹  Jimin Wang²  Alfred Labeja³  Peter Cherepanov³  Stephen Hare³ 

[1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America;Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America;Division of Medicine, St. Mary's Campus, Imperial College London, London, United Kingdom

关键词: HIV-1;    Crystal structure;    Dimers (Chemical physics);    Salt bridges;    HIV-2;    Viral structure;    Elution;    Point mutation;   

DOI  :  10.1371/journal.ppat.1000515

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Experimental evidence suggests that a tetramer of integrase (IN) is the protagonist of the concerted strand transfer reaction, whereby both ends of retroviral DNA are inserted into a host cell chromosome. Herein we present two crystal structures containing the N-terminal and the catalytic core domains of maedi-visna virus IN in complex with the IN binding domain of the common lentiviral integration co-factor LEDGF. The structures reveal that the dimer-of-dimers architecture of the IN tetramer is stabilized by swapping N-terminal domains between the inner pair of monomers poised to execute catalytic function. Comparison of four independent IN tetramers in our crystal structures elucidate the basis for the closure of the highly flexible dimer-dimer interface, allowing us to model how a pair of active sites become situated for concerted integration. Using a range of complementary approaches, we demonstrate that the dimer-dimer interface is essential for HIV-1 IN tetramerization, concerted integration in vitro, and virus infectivity. Our structures moreover highlight adaptable changes at the interfaces of individual IN dimers that allow divergent lentiviruses to utilize a highly-conserved, common integration co-factor.

【 授权许可】

CC BY